Apparatus and method for coating implantable devices

ABSTRACT

A method of forming a coating for an implantable medical device, such as a stent, is provided which includes applying a composition to the device in an environment having a selected pressure. An apparatus is also provided for coating the devices. The apparatus comprises a chamber for housing the device wherein the pressure of the chamber can be adjusted during the coating process.

[0001] This is a Continuation of U.S. Ser. No. 09/872,816, filed on May31, 2001, allowed.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to an apparatus and method for coatingimplantable devices such as stents.

[0004] 2. Description of the Background

[0005] Stents act as scaffoldings, functioning to physically hold openand, if desired, to expand the wall of the passageway. Typically, stentsare capable of being compressed, so that they can be inserted throughsmall cavities via catheters, and then expanded to a larger diameteronce they are at the desired location. Mechanical intervention viastents has reduced the rate of restenosis; restenosis, however, is stilla significant clinical problem. Accordingly, stents have been modifiedto perform not only as a mechanical scaffolding, but also to providebiological therapy.

[0006] Biological therapy can be achieved by medicating the stents.Medicated stents provide for the local administration of a therapeuticsubstance at the diseased site. In order to provide an efficaciousconcentration to the treated site, systemic administration of suchmedication often produces adverse or toxic side effects for the patient.Local delivery is a preferred method of treatment in that smaller totallevels of medication are administered in comparison to systemic dosages,but are concentrated at a specific site. Local delivery thus producesfewer side effects and achieves more favorable results.

[0007] A common method of medicating a stent is by depositing apolymeric coating, impregnated with the therapeutic substance, on thesurface of the stent. A polymer dissolved in a solvent is applied to thestent. A therapeutic substance can be dissolved or dispersed in thecomposition. The solvent is allowed to evaporate to form the coating.The application of the composition can be performed by spraying thecomposition on the stent or immersing the stent in the composition.

[0008] The solvents employed with the composition can be categorized ashaving a high vapor pressure or low vapor pressure. Non-volatilesolvents evaporate very slowly from the composition causing coatingdefects such as inconsistency in the coating thickness and formation of“cob webs” or “pool webs” between the stent struts. A solution to thisproblem is to coat the stent at elevated temperatures to increase theevaporation rate of the solvent. However, not all drugs are stable atelevated temperatures. Volatile solvents have the tendency to evaporatevery quickly from the composition resulting in a coating which has apowdered consistency and adheres poorly to the surface of the stent.Accordingly, what is needed is an apparatus and process for coatingstents that does not suffer from the aforementioned drawbacks.

SUMMARY OF THE INVENTION

[0009] In accordance with one aspect of the invention, a method offorming a coating for an implantable medical device, such as a stent, isprovided. The method comprises applying a composition to the stent in anenvironment having a pressure other than ambient pressure. Forcompositions including a non-volatile solvent, the pressure can be lessthat 760 torr; for compositions including a volatile solvent, thepressure can be greater than 760 torr. The composition can include apolymer, such as an ethylene vinyl alcohol copolymer dissolved in asolvent, such as dimethylacetamide. Optionally, a therapeutic substancecan be added to the composition, such as actinomycin D, paclitaxel,docetaxel, or rapamycin. In accordance to one embodiment, thecomposition can be applied by spraying the composition on the stent.During the act of applying, the stent can be rotated and/or moved in alinear direction along the longitudinal axis of the stent. The stent canbeta radially expandable stent, such as a balloon expandable orself-expandable type.

[0010] In accordance with another aspect of the invention, a method offorming a coating for a stent is provided, comprising positioning astent in a chamber; applying a fluid to the stent; and adjusting thepressure of the chamber to increase or decrease the evaporation rate ofthe fluid.

[0011] In accordance with another aspect of the invention, an apparatusfor coating implantable medical devices such as stents is provided. Theapparatus includes a chamber for housing a stent and a pressurecontroller for adjusting the pressure of the chamber during the coatingprocess to a pressure below or above 760 torr. In one embodiment, anapplicator can be provided for spraying a composition at the stent. Asupport assembly holds the stents in the chamber and can be connected toa motor for providing rotational and/or translational motion to thestent. A temperature controller can also be provided for adjusting thetemperature of the chamber.

BRIEF DESCRIPTION OF THE FIGURE

[0012]FIG. 1 illustrates a pressure chamber for forming a coating on astent.

DETAILED DESCRIPTION OF THE EMBODIMENTS Embodiments of the PressureChamber

[0013] Referring to FIG. 1, there is illustrated a pressure chamber 10defining a workspace 12 for depositing a composition on a stent 14 forforming a coating. A chamber opening (number omitted) can be providedfor allowing a user to gain access into workspace 12. A hatch 16 can beplaced over the chamber opening for tightly sealing the opening duringthe deposition process. The size of workspace 12 needs to be largeenough so as to enclose a support assembly 18, such as a mandrel, foradequately supporting stent 14 during the coating process. Workspace 12can be large enough so as to support any suitable number of supportassemblies 18 and stents 14.

[0014] In one embodiment, support assembly 18 can be connected to afirst motor assembly 20A for rotation of support assembly 18 along thecentral, longitudinal axis x of stent 14. A second motor assembly 20Bcan be additionally provided for translational movement of supportassembly 18 in a linear direction, back and forth, along a railing 22.The rotational and translational motion of stent 14 during theapplication of the composition can result in a more uniform depositionof the coating.

[0015] An applicator 24, such as a spray valve, penetrates through thewall of pressure chamber 10 and is positioned in the vicinity of stent14. Commercial applicators are available from Spray Systems Co., EFDInternational Inc., and Badger Air-Brush Co., one specific model ofwhich is the EFD 780S spray device with VALVEMATE 7040 control system.To avoid spray rate alterations due to the pressure difference,applicator 24 can be placed entirely within pressure chamber 10. Thenose of applicator 24 can be positioned at any suitable distance awayfrom stent 14, for example at about 1 cm to about 10 cm. An operatorshould be capable of adjusting the distance depending on the particularcircumstances of the deposition process. Applicator 24 is capable ofapplying the composition at a pressure of, for example, about 10 torr toabout 1000 torr. In accordance with an alternative embodiment, supportelement 18 can be in a vertical position and applicator 24 spraying in ahorizontal direction.

[0016] A pressure controller such as a pump 26 is in fluid communicationwith workspace 12 so as to create pressures below or above 760 torr (1atm) in pressure chamber 10. In one embodiment, a cold trap 28 can beprovided for preventing the solvent or condensation from penetratinginto pump 26 should pump 26 be used to create a vacuum in pressurechamber 10. A filter 30, such as a mist filter, can also be provided toprevent droplets of coating composition from possibly reaching anddamaging pump 26. Other components of pressure chamber 10 can include athrottle valve 32 for opening and closing the communication line to pump26, a baratron vacuum gauge 34 for measuring the pressure in workspace12 independent of the type and composition of the solvent vapor, and anabsorbent 36 for capturing the bulk of the composition over-spray. Gas,such as air, can be pumped or bled into pressure chamber 10 for creatinga convection flow inside pressure chamber 10, to actively scavenge thesolvent vapor from workspace 12 and out through pump 26 so as to preventsolvent vapor build-up. A diffuser 38 can be used to diffuse or “spreadout” the flow of gas so as to minimize disturbance of the sprayingprocess. A bleed valve 40 can be used for adjusting the flow rate of gasthrough diffuser 38. In addition to rapidly removing the solvent vaporfrom pressure chamber 10, bleed valve 40 can also be used to control thechamber pressure by working in concert with throttle valve 32.

[0017] Pressure chamber 10 can also be connected to a heating and/orcooling source 44 so as to control the temperature of workspace 12. Acooler deposition environment, such as temperatures of less than 50° C.may be preferred depending on the chemical stability of the therapeuticsubstance and the type solvent used. In lieu of providing an externalheating source, an internal component, such as heating and/or coolingcoils, can be provided.

Method of Applying the Composition

[0018] To form a coating on a surface of stent 14, the surface of stent14 should be clean and free from contaminants that may be introducedduring manufacturing. However, the surface of stent 14 requires noparticular surface treatment to retain the applied coating. Stent 14 ismounted on mandrel 18 and the composition is sprayed via applicator 24at a pressure of, for example between 10 to 1000 torr. During thespraying of the composition, stent can be rotated at about 1 to about120 rotations per minute. Stent 14 can also be moved in a lineardirection at speed of about 1 to about 20 cm/sec. The temperature ofchamber 10 should be maintained at a temperature that does not adverselyaffect the therapeutic substance or the coating process—for example atabout 20° C. to about 50° C.

[0019] For a solvent having a low vapor pressure (e.g., below 30 torr atthe temperature of application), or in other words non-volatilesubstances, the solvent evaporates very slowly from the composition,leading to irregularities in the coating thickness and “cob webs” or“pool webs” between the stent struts. Accordingly, compositions havebeen applied in short bursts, interrupted by the drying of thecomposition between each application step to minimize coating defects.Reducing the pressure of chamber 10 below ambient pressure during thecoating process allows the solvent to evaporate more rapidly. Rapidevaporation of the solvent allows the composition to be appliedcontinuously for depositing a coating of a suitable thickness or weightwhile minimizing coating defects such as “pool webs.” The pressureemployed in pressure camber 10 depends on the type of solvent employed.Table 1 is an exemplary list of non-volatile solvents and the suitablerange of pressure which can be used in the process of the presentinvention: TABLE 1 Exemplary Pressure Ranges Solvent torr @ 20° C.Dimethylsulfoxide 0.8-<760 Dimethlacetamide 0.9-<760 Dimethylformamide5.4-<760

[0020] For a solvent having a high vapor pressure (e.g., above 30 torrat the temperature of application), or in other words volatile solvents,the solvent evaporates extremely rapidly from the composition, leadingto difficulties in the application of the composition to the stent.Application of such compositions often lead to coatings having powderedconsistency and poor adhesion of the coating to the surface of thestent. Increasing the pressure in pressure chamber 10 above ambientpressure causes the solvent to evaporate more slowly leading to acoating with a smoother surface, more uniform composition, and betteradhesion. Table 2 is an exemplary list of volatile solvents and thesuitable range of pressure which can be used in the process of thepresent invention: TABLE 2 Exemplary Pressure Ranges Solvent torr @ 20°C. Toluene >760-2000 n-propanol >760-3400 Acetone >760-9000

The Composition

[0021] The embodiments of the composition can be prepared byconventional methods wherein all components are combined, then blended.More particularly, in accordance to one embodiment, a predeterminedamount of a polymer or combination of polymers can be added to apredetermined amount of a solvent or a combination of solvents. Ifnecessary, heating, stirring and/or mixing can be employed to effectdissolution of the polymer(s) into the solvent(s)—for example in an 80°C. water bath for two hours. A therapeutic substance can be also addedto the composition. The therapeutic substance should be in true solutionor saturated in the blended composition. If the therapeutic substance isnot completely soluble in the composition, operations including mixing,stirring, and/or agitation can be employed to effect homogeneity of theresidues. The therapeutic substance may be added so that dispersion isin fine particles. The mixing of the therapeutic substance can beconducted at ambient pressure and at room temperature.

[0022] The polymer or combination of polymers chosen must bebiocompatible and minimize irritation to the vessel wall when the deviceis implanted. The polymer may be either a biostable or a bioabsorbablepolymer. Bioabsorbable polymers that could be used includepoly(hydroxyvalerate), poly(L-lactic acid), polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), copoly(ether-esters) (e.g. PEO/PLA),polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid. Also,biostable polymers with a relatively low chronic tissue response such aspolyurethanes, silicones, and polyesters could be used. Other polymersinclude polyolefins, polyisobutylene and ethylene-alphaolefincopolymers; acrylic polymers and copolymers; vinyl halide polymers andcopolymers, such as polyvinyl chloride; polyvinyl ethers, such aspolyvinyl methyl ether; polyvinylidene halides, such as polyvinylidenefluoride and polyvinylidene chloride; polyacrylonitrile; polyvinylketones; polyvinyl aromatics, such as polystyrene; polyvinyl esters,such as polyvinyl acetate; copolymers of vinyl monomers with each otherand olefins, such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers; polyamides, such as Nylon 66 and polycaprolactam; alkydresins; polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxyresins; polyurethanes; rayon; rayon-triacetate; cellulose, celluloseacetate; cellulose butyrate; cellulose acetate butyrate; cellophane;cellulose nitrate; cellulose propionate; cellulose ethers; andcarboxymethyl cellulose. Ethylene vinyl alcohol is functionally a verysuitable choice of polymer. The copolymer possesses good adhesivequalities to the surface of a stent, particularly stainless steelsurfaces, and has illustrated the ability to expand with a stent withoutany significant detachment of the copolymer from the surface of thestent. The copolymer, moreover, allows for good control capabilitiesover the release rate of the therapeutic substance.

[0023] Representative examples of solvents include chloroform, acetone,water (buffered saline), dimethylsulfoxide (DMSO), propylene glycolmethyl ether (PM,) isopropyl alcohol (IPA), n-propyl alcohol, methanol,ethanol, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC), benzene, toluene, xylene, hexane, cyclohexane,heptane, octane, nonane, decane, decalin, ethyl acetate, butyl acetate,isobutyl acetate, isopropyl acetate, butanol, diacetone alcohol, benzylalcohol, acetone, 2-butanone, cyclohexanone, dioxane, methylenechloride, carbon tetrachloride, tetrachloroethylene, tetrachloroethane,chlorobenzene, 1,1,1-trichloroethane, formamide, and combinationthereof. The solvent should be capable of placing the selected polymerinto dissolution at the selected concentration and should not adverselyreact with the therapeutic substance.

[0024] The therapeutic substance can include any agent capable ofexerting a therapeutic or prophylactic effect in the practice of thepresent invention such as inhibition of migration and/or proliferationof smooth muscle cells. The agent can also be for enhancing woundhealing in a vascular site and improving the structural and elasticproperties of the vascular site. Examples of agents includeantiproliferative substances as well as antineoplastic,antiinflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin,antimitotic, antibiotic, antioxidant, and combinations thereof. Onesuitable example of an antiproliferative substance includes actinomycinD—synonyms of which include dactinomycin, actinomycin IV, actinomycinI₁, actinomycin X₁, and actinomycin C₁. Examples of suitableantineoplastics include paclitaxel and docetaxel. Examples of suitableantiplatelets, anticoagulants, antifibrins, and antithrombins includesodium heparin, low molecular weight heparin, hirudin, argatroban,forskolin, vapiprost, prostacyclin and prostacyclin analogs, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIa platelet membrane receptor antagonist, recombinanthirudin, thrombin inhibitor (available from Biogen), and 7E-3B® (anantiplatelet drug from Centocore). Examples of suitable antimitoticagents include methotrexate, azathioprine, vincristine, vinblastine,fluorouracil, adriamycin, and mutamycin. Examples of suitable cytostaticor antiproliferative agents include angiopeptin (a somatostatin analogfrom Ibsen), angiotensin converting enzyme inhibitors such as CAPTOPRIL(available from Squibb), CILAZAPRIL (available from Hoffman-LaRoche), orLISINOPRIL (available from Merck); calcium channel blockers (such asNifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonist, LOVASTATIN (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug from Merck),monoclonal antibodies (such as PDGF receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitor (available formGlazo), Seramin (a PDGF antagonist), serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. Other therapeutic substances or agents which may beappropriate include alpha-interferon, genetically engineered epithelialcells, rapamycin, and dexamethasone.

[0025] The dosage or concentration of the active agent required toproduce a favorable therapeutic effect should be less than the level atwhich the active agent produces toxic effects and greater than the levelat which non-therapeutic results are obtained. The dosage orconcentration of the active agent required to inhibit the desiredcellular activity of the vascular region can depend upon factors such asthe particular circumstances of the patient; the nature of the trauma;the nature of the therapy desired; the time over which the ingredientadministered resides at the vascular site; and if other therapeuticagents are employed, the nature and type of the substance or combinationof substances. Therapeutic effective dosages can be determinedempirically, for example by infusing vessels from suitable animal modelsystems and using immunohistochemical, fluorescent or electronmicroscopy methods to detect the agent and its effects, or by conductingsuitable in vitro studies. Standard pharmacological test procedures todetermine dosages are understood by one of ordinary skill in the art.

[0026] Stent is broadly intended to include self-expandable stents,balloon-expandable stents, and stent-grafts. One of ordinary skill inthe art, however, understands that other medical devices on which apolymer can be coated can be used with the practice of the presentinvention, such as grafts (e.g., aortic grafts), endocardial leads,valves, and the like. The underlying structure of the device can bevirtually any design. Stents are typically defined by a tubular bodyhaving a plurality of bands or cylindrical elements interconnected byconnecting elements. The device can be made of a metallic material or analloy such as, but not limited to, cobalt chromium alloy (ELGILOY),stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE (Nitinol),tantalum, nickel-titanium alloy, platinum-iridium alloy, gold,magnesium, or combinations thereof. “MP35N” and “MP20N” are trade namesfor alloys of cobalt, nickel, chromium and molybdenum available fromstandard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devicesmade from bioabsorbable or biostable polymers could also be used withthe blended composition.

[0027] While particular embodiments of the present invention have beenshown and described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from theembodiments this invention in its broader aspects and, therefore, theappended claims are to encompass within their scope all such changes andmodifications as fall within the true spirit and scope of theembodiments this invention.

[0028] This is a continuation of U.S. Ser. No. 09/872,816, the entiredisclosure of which is incorporated by reference.

What is claimed is:
 1. A method of forming a coating for an implantablemedical device, comprising a) inserting the device into a chamber; b)adjusting the pressure of the chamber to a pressure other than ambientpressure; c) applying a composition comprising a solvent to theimplantable device while the device is disposed in an environment havingthe pressure at other than ambient pressure wherein the pressure isgreater than 760 torr if the solvent evaporation rate is to bedecreased, and alternatively, wherein other than ambient pressure isless than 760 torr if the solvent evaporation rate is to be increased.2. The method of claim 1 wherein the composition comprises a polymerdissolved in the solvent and optionally a therapeutic substance addedthereto.
 3. The method of claim 2 wherein the therapeutic substance isactinomycin D, paclitaxel, docetaxel, or rapamycin.
 4. The method ofclaim 2 wherein the solvent comprises a compound selected fromchloroform, acetone, water, buffered saline, dimethylsulfoxide,propylene glycol methyl ether, isopropyl alcohol, n-propyl alcohol,methanol, ethanol, tetrahydrofuran, dimethylformamide, dimethylacetamide, benzene, toluene, xylene, hexane, cyclohexane, heptane,octane, nonane, decane, decalin, ethyl acetate, butyl acetate, isobutylacetate, isopropyl acetate, butanol, diacetone alcohol, benzyl alcohol,acetone, 2-butanone, cyclohexanone, dioxane, methylene chloride, carbontetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene,1,1,1-trichloroethane, formamide, and their combinations.
 5. The methodof claim 1 wherein the act of applying comprises spraying thecomposition on the implantable device.
 6. The method of claim 1 whereinthe implantable device is a stent and the act of applying comprisesspraying the composition while rotating the stent about the longitudinalaxis of the stent.
 7. The method of claim 1 wherein the implantabledevice is a stent and the act of applying comprises spraying thecomposition while moving the stent in a linear direction along thelongitudinal axis of the stent.
 8. The method of claim 1 wherein thecomposition includes a therapeutic substance and wherein the temperatureof the chamber is adjusted to a temperature that does not adverselyaffect the therapeutic substance.
 9. The method of claim 8 wherein thecomposition comprises a polymer dissolved in the solvent.
 10. A methodof forming a coating for an implantable medical device, comprising a)inserting the device into a chamber; b) adjusting the pressure of thechamber to a pressure other than ambient pressure; c) applying acomposition comprising a solvent to the implantable device while thedevice is disposed in an environment having the pressure at other thanambient pressure wherein the pressure is selected based on the vaporpressure of the solvent.
 11. The method of claim 10 wherein thecomposition comprises a polymer dissolved in the solvent and optionallya therapeutic substance added thereto.
 12. The method of claim 11wherein the therapeutic substance is actinomycin D, paclitaxel,docetaxel, or rapamycin.
 13. The method of claim 11 wherein the solventcomprises a compound selected from chloroform, acetone, water, bufferedsaline, dimethylsulfoxide, propylene glycol methyl ether, isopropylalcohol, n-propyl alcohol, methanol, ethanol, tetrahydrofuran,dimethylformamide, dimethyl acetamide, benzene, toluene, xylene, hexane,cyclohexane, heptane, octane, nonane, decane, decalin, ethyl acetate,butyl acetate, isobutyl acetate, isopropyl acetate, butanol, diacetonealcohol, benzyl alcohol, acetone, 2-butanone, cyclohexanone, dioxane,methylene chloride, carbon tetrachloride, tetrachloroethylene,tetrachloroethane, chlorobenzene, 1,1,1-trichloroethane, formamide, andtheir combinations.
 14. The method of claim 10 wherein the act ofapplying comprises spraying the composition on the implantable device.15. The method of claim 10 wherein the implantable device is a stent andthe act of applying comprises spraying the composition while rotatingthe stent about the longitudinal axis of the stent.
 16. The method ofclaim 10 wherein the implantable device is a stent and the act ofapplying comprises spraying the composition while moving the stent in alinear direction along the longitudinal axis of the stent.
 17. Themethod of claim 1 wherein the composition includes a therapeuticsubstance and wherein the temperature of the chamber is adjusted to atemperature that does not adversely affect the therapeutic substance.18. The method of claim 17 wherein the composition includes a polymerdissolved in the solvent.